DE69732369T2 - VITAMIN D3 DERIVATIVES - Google Patents

Abstract

A compound of formula (I) in which formula Q is a C1-C6 hydrocarbylene diradical; Y is either a single bond, a carbonyl group or a methylene, ethylene, -CH(OH)-, -O-(C 6 H 4)- (ortho, meta, para) or -S-(C 6 H 4)-(ortho, meta, para) diradical; R 1 and R 2, which may be the same or different, stand for hydrogen or a C 1 -C 6 hydrocarbyl radical; or R 1 and R 2 , when taken together with the carbon atom (starred in formula 1) bearing the group Z, can form a C 3 -C 6 carbocyclic ring; and Z is hydrogen or hydroxy; with the proviso that when, at the same time, Q is ethylene Y is methylene, R 1 and R 2 stand for methyl or trifluoromethyl, and Z is hydroxy, or when, at the same time, Q is ethylene, Y stands for carbonyl or -CH(OH)-, R 1 and R 2 are methyl, and Z is hydroxy, then the configuration at C-20 cannot be E. The compounds show anti-inflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells.

Description

The The present invention relates to a hitherto unknown class of Compounds that have a strong activity regarding the induction of differentiation and the inhibition of unwanted Proliferation of certain cells, including cancer cells and Skin cells, as well as anti-inflammatory and immunomodulatory effects; pharmaceutical preparations, containing these compounds; Dosage units of these preparations and their use for the treatment and prophylaxis of hyperparathyroidism, especially secondary renal failure-related hyperparathyroidism, Diseases characterized by abnormal cell differentiation and / or Characterize cell proliferation, such as cancer, leukemia, myelofibrosis and psoriasis, a series of pathological conditions, including diabetes mellitus, high blood pressure, acne, alopecia, Skin aging, AIDS, neurodegenerative diseases such as Alzheimer's disease, Host versus graft reactions, Transplant rejection, inflammatory Diseases such as rheumatoid arthritis and asthma, for prevention and / or treatment of steroid-induced skin atrophy, and to Increase osteogenesis and treatment of osteoporosis.

worin Q für einen zweiwertiger C₁-C₆-Kohlenwasserstoffrest steht; Y entweder für eine Einfachbindung, eine Carbonylgruppe oder einen zweiwertigen Methylen-Rest, Ethylen-Rest, -CH(OH)-Rest, -O-(C₆H₄)-Rest (ortho, meta, para) oder -S-(C₆H₄)-Rest (ortho, meta, para) steht; R¹ und R², die gleich oder verschieden sein können, für Wasserstoff oder einen C₁-C₆-Kohlenwasserstoffrest stehen; oder R¹ und R² zusammen mit dem die Gruppe Z tragenden Kohlenstoffatom (in Formel I mit * gekennzeichnet) einen C₃-C₆-carbocyclischen Ring bilden können; und Z Wasserstoff oder Hydroxy ist; mit der Maßgabe, dass die Konfiguration am C-20 nicht R sein kann, falls Q Ethylen, Y Carbonyl oder -CH(OH)-, R¹ und R² Methyl und Z Hydroxy sind.The compounds according to the invention have the general formula I:

wherein Q is a divalent C ₁ -C ₆ hydrocarbon radical; Y is either a single bond, a carbonyl group or a divalent methylene radical, ethylene radical, -CH (OH) radical, -O- (C ₆ H ₄ ) radical (ortho, meta, para) or -S- ( C ₆ H ₄ ) radical (ortho, meta, para); R ¹ and R ² , which may be the same or different, are hydrogen or a C ₁ -C ₆ hydrocarbon radical; or R ¹ and R ² together with the carbon atom bearing the group Z (marked with * in formula I) can form a C ₃ -C ₆ -carbocyclic ring; and Z is hydrogen or hydroxy; with the proviso that the configuration at C-20 can not be R if Q is ethylene, Y is carbonyl or -CH (OH) -, R ¹ and R ^{2 are} methyl and Z is hydroxy.

in the For the purposes of this invention, the term hydrocarbon radical is used (divalent hydrocarbon radical) for the remainder after removal of 1 (2) hydrogen atoms) from a straight-chain, branched or cyclic, saturated or unsaturated Hydrocarbon is formed.

Examples of Q include methylene, ethylene, tri-, tetra- and pentamethylene, -CH = CH-, -CH = CH-CH = CH-, -CH = CH-C≡C-, -CH = CH-CH ₂ -, -CH ₂ - (C ₆ H ₄ ) - (ortho, meta, para), -C≡C-, -C≡C-CH ₂ -, -CH (R) - (CH ₂ ) ₂ , -CH (R) -CH = CH-, and -CH (R) -C≡C-, wherein R is hydroxy, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkyl, but is not limited thereto. Of particular interest are compounds of the formula I in which Q is - (CH ₂ ) _n -, where n is an integer from 1 to 4, or for a straight-chain carbon chain having one or two, in the latter case conjugated, double or triple bonds or for -CH (R) -C≡C-, where R is as defined above.

R ¹ and R ^{2 taken} together may be, for example, but not limited to, hydrogen, methyl, ethyl, vinyl, n-, iso- and cyclopropyl, and trifluoromethyl.

R ¹ and R ² may together be, for example, di-, tri-, tetra- and pentamethylene.

The Compounds of the invention include more than one stereoisomeric form (e.g., R or S configuration at the C-20, E or Z configuration, if a double bond in the Group Q is present). The invention includes all of these stereoisomers in pure form and mixtures thereof.

in addition comes that the compounds of the invention, in which one or more hydroxy groups are masked as groups, which can be converted back to hydroxy groups in vivo, prodrugs of I am.

links of formula I, in which Z is hydrogen, may also be used as prodrugs act as these compounds are comparatively inactive in vitro, by enzymatic hydroxylation but to active compounds of Formula I can be converted after being administered to the patient.

It is known that 1α, 25-dihydroxy-vitamin D ₃ (1,25 (OH) ₂ D ₃ ) influences the effects and / or production of interleukins (Muller, K. et al., Immunol, Lett., 17, 361-366 (1988)), indicating the potential use of this compound for the treatment of disorders characterized by immune system dysfunction such as autoimmune diseases, AIDS, host-versus-graft reactions and transplant rejection, or other conditions, characterized by abnormal interleukin-1 production, eg, inflammatory diseases such as rheumatoid arthritis and asthma.

It is also known that 1,25 (OH) ₂ D _{3 is} able to stimulate differentiation of cells and to inhibit excessive cell proliferation (Abe, E. et al., Proc. Natl. Acad. Sci. USA, 78, 4990-4994 (1981)); It has been suggested that this compound could be useful in the treatment of disorders characterized by abnormal cell proliferation and / or differentiation, such as leukemia, myelofibrosis and psoriasis.

It has also been reported to use 1,25 (OH) ₂ D ₃ , or its prodrug 1α-OH-D _3, for the treatment of hypertension (Lind, L. et al., Acta Med. Scand., 222, 423-427 ( 1987)) and diabetes mellitus (Inomata, S. et al., Bone Mineral, 1, 187-192 (1986)). Another indication for 1,25 (OH) ₂ D ₃ is suggested by the recent observation of an association between hereditary vitamin D resistance and alopecia: Treatment with 1,25 (OH) ₂ D ₃ may stimulate hair growth (Editorial, Lancet , March 4, p. 478 (1989)). Also, the fact that topical application of 1,25 (OH) ₂ D ₃ reduces the size of the sebaceous glands in the ears of male golden hamsters suggests that this compound may be useful in the treatment of acne (Malloy VL et al., The Tricontinental Meeting for Investigative Dermatology, Washington, (1989)).

However, the therapeutic possibilities in such indications are considerably limited by the well-known potent effect of 1,25 (OH) ₂ D ₃ on calcium metabolism; elevated blood levels rapidly lead to hypercalcaemia. Therefore, this compound and some of its potent synthetic analogs are unsatisfactory for use as medicaments for the treatment of, for example, psoriasis, leukemia or immune disorders, which may require the continuous administration of the drug in relatively high doses.

Recently a number of vitamin D analogues have been described in vitro a certain degree of selectivity in favor of cell differentiation inducing or cell proliferation inhibitory effect compared to those safely administered Dose-reducing in vivo effects on calcium metabolism (determined by increased Serum calcium concentration and / or increased calcium excretion in the Urine) show. One of the first of these, Calcipotriol (INN) or Calcipotriene (USAN), has been developed on the basis of this selectivity and applies now worldwide as an effective and safe medicine for topical Treatment of psoriasis.

A Examination with another analog selected on this basis (EB 1089) supports this Concept that systemically administered vitamin D analogues in vivo in subtoxic doses can inhibit breast cancer cell proliferation (Colston, K.W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992) and Mathias, I.S. et al., J. Steroid Biochem. Molec. Biol., 46, 365-371 (1993)).

There are summaries of promising immunosuppressive activities of vitamin D analogs (Binderup, K., Biochem Pharamcol 43, 1885-1892 (1992)). Thus, a series of 20-epi-vitamin D analogues have been found to be potent inhibitors of T lymphocyte activation in vitro (Binderup, L. et al., Biochem Pharmacol., 42, 1569-1575 (1991)). Two of these analogs, MC 1288 and KH 1060, show in vivo immunosuppressive activities when given systemically in animal models. It has also been shown that KH 1060, alone or in combination with cyclosporin A, in diabetic NOD mice can prevent autoimmune destruction of transplanted islet cells (Bouillon, R. et In: Vitamin D, a Pluripotent Steroid Hormones: Structural Studies, Molecular Endocrinology and Clinical Applications; Norman, A. W. Bouillon, R., Thomasset, M., Eds .; de Gruyter, Berlin, 1994 pp. 531-552). MC 1288 has been shown to prolong the survival of cardiac and small intestinal transplants in rats (Johnsson, C. et al., In Vitamin D, Pluripotent Steroid Hormones: Structural Studies, Molecular Endocrinology and Clinical Applications, Norman, AW Bouillion, R., Thomasset , M., eds. De Gruyter, Berlin, 1994 S. 549-550). In all of these studies, however, doses of the analogs that resulted in significant immunosuppression also induced elevated serum calcium levels. Therefore, there is a continuing need for new analogs with an acceptable combination of prolonged therapeutic activity and minimal toxic effects.

The compounds of the present invention provide a previously undisclosed series of 16-dehydro-1α, 25-dihydroxy-vitamin D ₃ analogues having potent immunosuppressive and cell proliferation inhibitory activities. Characteristic of the compounds of the formula I is the presence of a 16,17-double bond in the five-membered ring D; their absolute configuration on the C-20 can be either R or S.

Analogs of vitamin D with a 16,17 double bond in ring D are not new. For example, Hoffmann-La Roche Inc. in U.S. Patents 5,087,619 / 1992 and 5,145,846 / 1992 describes the synthesis and use of 25-hydroxy and 1α, 25-dihydroxy-16-ene-cholecalciferols, 23-ene and 23-yn Analogs thereof as well as corresponding 26,26,26,27,27,27-hexafluoro derivatives. Uskokovic, MR et al. describe the synthesis and biological activities of the 16-ene analogues of 1,25-dihydroxycholecalciferol (In: Vitamin D, Gene Regulation, Structure-Function Analysis and Clinical Application, Norman, AW Bouillion, R., Thomasset, M., eds. de Gruyter, Berlin, 1991 pp. 139-145). Hoffmann-La Roche AG, in European Patent Application 0580968/1993, describes the synthesis and use of 26,26,26,27,27,27-hexafluoro analogs of 25-hydroxy-1α, 25-dihydroxy and 1a-fluoro-25 -hydroxy-16-en-23-in-cholecalciferols and their corresponding 19-nor derivatives. McLane, JA et al. describe stable and active metabolites of 1,25-dihydroxy-16-en-cholecalciferol (US Pat. No. 5,401,733 / 1995). However, it should be noted that these and other prior art 16-dehydro-vitamin D compounds are characterized by the presence of the natural vitamin D ₃ configuration of the C-20 methyl group. Furthermore, they all have the six-carbon aliphatic backbone of the natural vitamin D ₃ side chain as the remainder of the side chain (the other substituent on C-20). Finally, these compounds optionally contain a 23,24 double or triple bond.

The compounds of the invention differ from the prior art 16-dehydro-vitamin D ₃ analogs by the backbone of the C-20 side chain, which is not limited to being either aliphatic or having six carbon atoms, and in position of the optional double or triple bond (s), which is not limited to lie between the carbon atoms 23 and 24. In addition, the configuration at C-20 may be either R (the configuration of natural vitamin D) or S.

For the purpose of Evidence of the effectiveness of the compounds of formula 1 is on the information in Table A indicates: the meaning of "HaCaT, rel. "," MLR, rel. ", and" Calc., rel. "below explained.

A useful assay to classify the test compounds for their antiproliferative activity in skin cells, eg, their anti-psoriatic activity, is the in vitro assay using HaCaT, a spontaneously immortalized, non-tumorigenic, human dermal keratinocyte cell line (Mørk Hansen, C et al., Invest Dermatol., 1, 44-48 (1996)), measuring ³ H-thymidine uptake.

One in vitro assay to classify the test compounds for their immunosuppressive potency is the mixed lymphocyte reaction assay, "MLR", which measures the allogeneic stimulation of mouse spleen lymphocytes: one stimulates lymphocytes derived from BALB / c- and spleen CB6F1 mice was cultured by co-culturing 5 x 10 ⁶ / ml cells from BALB / c mice (responders) with 7.5 x 10 ⁶ / ml cells from CB6F1 mice (inducer) .The mixed cultures of lymphocytes were incubated one 72 hours with the test compounds.The cellular DNA synthesis is assessed by the incorporation of ³ H-thymidine in the DNA.

In general, the classical effects of 1,25 (OH) ₂ D ₃ on calcium balance in the organism, including calcemic and calcic activities, are undesirable for the vitamin D analogs of the invention; Normally, for this selectivity, for example, in favor of the proliferation inhibition of certain cells and / or immunosuppressive activity is desired.

The calcemic activity of the compounds in vivo was determined in rats as described previously (Binderup, LL., Bramm, E., Biochem Pharmacol., 37, 889-895 (1988)). In Table A, column "Calc., Rel. "indicates the calcemic activities of selected compounds (relative to 1,25 (OH) ₂ D ₃ ), as noted, low values are usually preferred for the compounds of this invention.

It can be seen from Table A that the selected compounds 107 and 111 in the HaCaT assay (psoriasis model) are much more potent than 1,25 (OH) ₂ D ₃ , while the calcemic activity is that of 1,25 (OH) ₂ D _{3 is} similar.

What the further important property of the compound according to the invention, their immunosuppressive activity, from Table A, column "MLR, rel.", it can be seen that the compounds selected 107 and 111 have strong effects.

Table A: Biological Tests of Compounds I and Comparative Compounds

Notes on table A

• * The rest of the molecule is the same as in formula I.
• ** The values are based on 1.25 (OH) ₂ D ₃ ; a value greater than 1 represents a compound that is more active in the assay than 1.25 (OH) ₂ D ₃ .
• Calculated as the ratio of the IC ₅₀ value of 1.25 (OH) ₂ D ₃ and the IC ₅₀ value of the compound, IC _{50 being} the concentration that compares to a 50% inhibition of ³ H-thymididine incorporation leads to the controls.
• # 1.25 = 1.25 (OH) ₂ D ₃ = 1.25 (OH) ₂ vitamin D ₃ .

  nd

  = not determined

  Ref.

  Comparative compound

The Compounds of the formula I can from the epimeric C-20 alcohols 3 and 4, for example with the general methods of Schemes 1 and 2 are prepared; from this, starting from the vitamin D-derived aldehyde 1 (Calverley, M.J., Tetrahedron, 43, 4609-4619 (1987)) the 20-keto compound 2 ongoing synthesis has been reported (Hansen, K. et al., In: Vitamin D: Gene Regulation, Structure Function Analysis and Clinical Application; Norma, A.W., Bouillon, R., Thomassset, M., eds .; de Gruyter, Berlin, 1991, pp. 161-162).

More accurate said, the preparation of the 16-Dehydrotosylate 13/14 and the analogous aldehydes 15/16, important intermediates in the synthesis the compounds of the formula I from said starting materials, outlined in Scheme 1 during the further implementation of the above key intermediates to the Compounds of the formula I in Scheme 2 is outlined.

to Synthesis of side chain building blocks V to VIII or analogs thereof you can proceed by default, as in the literature or the international patent applications WO 87/00843, WO 89/10351, WO 91/00271, WO 91/00855, WO 91/15475, WO 93/19044 and WO 95/02577.

The following standard abbreviations are used throughout the following description: DMF = N, N-dimethylformamide; DMSO = dimethyl sulfoxide; Et = ethyl; Hal = Halogen; "HF" = 5% hydrogen fluoride in acetonitrile: water (7: 1, v / v); Me = methyl; Ph = phenyl; PPTS = Pyridinium p-toluenesulfonate; TBAF = tetra-n-butylammonium fluoride trihydrate; TBDMS = tert-butyldimethylsilyl; THF = tetrahydrofuran; THP = tetrahydro-4H-pyran-2-yl; TMS = trimethylsilyl; Ts = p-toluenesulfonyl (tosyl).

Scheme 1

Notes on scheme 1

• a) dehydrogenation with phosphorus oxychloride in pyridine; 0 ° C / 1 h and then 20 ° C / 16-18 h.
• b) protecting the triene system with sulfur dioxide in dichloromethane / H ₂ O; 20 ° C / 45-90 min; chromatographic separation of the C-6 epimers.
• c) Carbonylation reaction with paraformaldehyde / boron trifluoride etherate in dichloromethane; 0 ° C / 5-20 min.
• d) deprotecting the SO ₂ adduct with sodium bicarbonate in toluene / H ₂ O; 90 ° C / 1-2 h.
• e) tosylation with p-toluenesulphonyl chloride in pyridine; 0-5 ° C / 16-18 h.
• f) Swern oxidation with oxalyl chloride / DMSO in dichloromethane; -78 ° C / 20 min.

Scheme 2

Q, Y, R ¹ and R ² and Z are as defined above; Z ¹ is hydroxy or a protected alcohol such as TMS-O, TBDMS-O, DPMS-O or THP-O; X is O or S; and n is 2, 3 or 4.

Notes on scheme 2

• a) Alkylation with the side-chain building block V (H-X-R3, see below) in the presence of base (sodium hydride) in DMF; 20 ° C / 0.5-22 h.
• b) reaction with the Grignard reagent R ⁴ -Mg-Hal, derived from side-chain building block VI (R ⁴ -Hal, see below) in the presence of Li ₂ CuCl ₄ in THF; 0 ° C / 2 h and then 8-10 ° C / 16-20 h.
• c) Reaction with the ylide A ¹ -R ⁵ , derived from side-chain building block VII (AR ⁵ , see below) in the presence of base (lithium bis (trimethylsilyl) amide) in THF; -45 ° C / 0.5-1.5 h.
• d) reaction with the ylide A ¹ -R ⁶ , derived from the side-chain building block VIII (A ¹ -R ⁶ , see below) at elevated temperature in toluene; 90-110 ° C / 2-8 h.
• e) Optional modification of the functional group in the side chain of compounds II.
• f) isomerization of the compounds IIa and III to the corresponding Compounds IV by means of UV light in the presence of a triplet sensitizer, e.g. Anthracene or 9-acetylanthracene.
• g) Deprotect Compounds IV to the corresponding compounds I, e.g. by Treatment with TBAF or "HF".
• HXR ³ V R ³ = - (C ₆ H ₄ ) -C (R ¹ ) (R ² ) -Z ¹ (o-, m-, p-)
• R ⁴ -Hal VI R ⁴ = -CH ₂ - (CH ₂ ) _n -C (R ¹ ) (R ² ) -Z ¹ Hal = Cl or Br
• AR ⁵ VII A = Ph ₃ P ⁺ - ^- CH ₂ or (EtO) ₂ P (O) -CH ₂ - R ⁵ = -CH = CH-CO-OMe
• AR ⁶ A as defined above
  

In A ¹ -R ⁵ and A ¹ -R ⁶ , A ^{1 is} Ph ₃ P ⁺ - ^- CH- or (EtO) ₂ P (O) -CHLi-, R ⁵ and R ⁶ are as defined above.

The Compounds of the invention are intended for use in pharmaceutical compositions, for local or systemic treatment of human and veterinary medicine Diseases are suitable as described above.

The Compounds of the invention can used in combination with other medicines or treatments become. In the treatment of psoriasis, the compounds of the invention e.g. in combination with steroids or with other treatments, e.g. a light or UV treatment or the combined PUVA treatment used become. In the treatment of cancer, the compounds of the invention in combination with other anti-tumor or anti-tumor treatments, as an irradiation treatment. In prevention against transplant rejection and graft-versus-host reaction or the treatment of autoimmune diseases can the compounds of the invention advantageous in combination with other immunosuppressive or immunoregulatory Drugs or treatments, e.g. with cyclosporin A, used become.

The required amount of a compound of formula I (hereinafter as active ingredient) for a Therapeutic effect naturally varies with both the respective Compound, the route of administration and the mammal to be treated. The Compounds of the invention can over the parenteral, intra-articular, enteral or topical route. You will be fine absorbed when administered enterally; this is the preferred one Route of administration in the treatment of systemic diseases. at the treatment of dermatological diseases such as psoriasis or Eye diseases are preferred for topical or enteral forms.

Although the administration of only the active substance as a raw chemical is possible, it is preferred to present this as a pharmaceutical formulation. Conveniently, the active ingredient is 0.1 ppm to 0.1% by weight of the formulation.

The formulations according to the invention, as well as veterinary as well as human medical use thus an active ingredient in conjunction with a pharmaceutically acceptable Carrier for it and if necessary (a) other therapeutic ingredient (s). The carrier (s) must be "compatible" in the sense that they are compatible with the other ingredients of the formulations and for their recipients are not harmful are.

To belong to the formulations e.g. those in an oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intraarticular and topical, nasal or buccal administration of appropriate form.

Under The term "dosage unit" is a standardized Dose, i. a single dose, understood, administered to a patient can be, is easy to handle and can be packed and received as a physically and chemically stable dosage unit remains, either the active substance as such or a mixture of which with solid or liquid pharmaceutical diluents or carriers includes.

The Formulations can expediently be presented in the form of dosage units and can after any methods known in the pharmaceutical field become. In all procedures, the active ingredient is associated with the carrier brought, which consists of one or more excipients. In general The formulations are prepared by mixing the active ingredient evenly and intimately associated with a liquid carrier or a finely divided solid support or both then, if necessary, shaping the product into the desired formulation.

Formulations of the invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or lozenges, each containing a quantity of active ingredient; in the form of a powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion available. The active ingredient may also be administered in the form of a bolus, electuary or paste.

formulations for rectal administration in the form of a suppository containing the active substance and a carrier, or in the form of an enema.

to parenteral administration suitable formulations include a sterile oily or aqueous preparation of the active ingredient, preferably isotonic with the blood of the recipient is. Percutaneous formulations can in the form of a plaster.

to intra-articular or ophthalmic administration suitable formulations may be disclosed in U.S. Pat Form of a sterile aqueous Preparation of the active substance, which may be microcrystalline, e.g. in the form of an aqueous microcrystalline suspension. Liposomal formulations or biological degradable polymer systems can also be used to the drug for both intra-articular as ophthalmic administration too.

to suitable formulations for topical or ophthalmic administration include liquid or semi-liquid Preparations such as liniments, lotions, gels, applicators, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions like Drops.

to Administration to the nose or oral cavity include powders, propellant-containing and spray formulations such as aerosols and atomizers.

Next the aforementioned components can the formulations according to the invention contain one or more other ingredients, such as diluents, Binders, preservatives, etc.

The Compositions can Furthermore contain other therapeutically active agents, which conventionally used for the treatment of the above-mentioned disease states like other immunosuppressants for the treatment of immunological Diseases, or steroids for the treatment of dermatological diseases.

The The present invention relates to the use of the compounds of the invention for the manufacture of a medicament for the treatment of patients, who suffer from any of the conditions mentioned above, where you need treatment Patients an effective amount of one or more compounds of Formula I, alone or in conjunction with one or more others conventionally used to treat the above-mentioned conditions administered therapeutically active compounds. The treatment with the compounds according to the invention and / or with other therapeutically active compounds can simultaneously or intermittently.

at The systemic treatment will be daily doses of 0.001-2 μg per kilogram Body weight, preferably 0.002-0.3 μg / kg body weight of a mammal, for example, 0.003-0.3 μg / kg of one Compound of formula I administered, usually a daily dose for one Adults from 0.2 to 25 μg correspond. For the topical treatment of dermatological diseases are administered ointments, creams or lotions, the 0.1-500 micrograms / g and preferably 0.1-100 μg / g of a Compound of formula I included. For topical use in the Ophthalmology is administered to ointments, drops or gels, which 0.1-500 μg / g and preferably 0.1-100 μg / g of a Compound of formula I included. The oral compositions become preferably formulated as tablets, capsules or drops, the 0.05-50 μg, preferably 0.1-25 μg, one Contain compound of formula I per dosage unit.

The Invention will now be described in more detail below described:

General procedures, Preparations and examples

General

The Example compounds of the formula I are listed in Table 5, while the Intermediates 5 to 16 and the compounds of the general formulas II, III and IV are listed in Tables 1 to 4.

The nuclear magnetic resonance spectra (300 MHz) show the chemical shift values (δ) for deuterochloroform solutions based on internal tetramethylsilane (δ = 0) or chloroform (δ = 7.25) specified. The value of a multiplet that is either defined (doublet (d), triplet (t), quartet (q)), or undefined (m) is given at the approximate midpoint, unless an area is specified (s = singlet, b = broad ). The coupling constants (J) are given in hertz (Hz) and sometimes rounded to the nearest integer value.

Ether is diethyl ether; he was dried over sodium. THF was dried over sodium benzophenone. Petroleum ether refers to the pentane fraction. The reactions were usually carried out under argon atmosphere at room temperature, unless otherwise specified. In the workup indicated, dilute with the indicated solvent (otherwise the organic reaction solvent), extract with water and then brine, dry over anhydrous MgSO ₄ and concentrate in vacuo to a residue. Chromatography was carried out on silica gel.

TABLE 1 Intermediate Compounds of Formulas 5-16 (Scheme 1)

General method

General procedure 1: dehydration of compounds 4 and 3 to the corresponding Anhydro compounds 5 and 6 (Preparations 1-2)

A solution Compound 4 (or) 3 (2.81 g, 5 mmol) in pyridine (40 mL) was cooled at 0 ° C and dripped while stirring within 5 minutes phosphorus oxychloride (4.6 ml, 50 mmol). you stir one hour at the low temperature and 16 hours at the ambient temperature, The reaction mixture was poured into ice-cold ethyl acetate (120 mL) and gave with stirring Add water (40 ml) carefully. It was in the mixture an apparent pH of 2.8 by addition of 4N hydrochloric acid (80 ml) and separated the phases. After a further extraction of the aqueous layer with ethyl acetate (60 ml) was worked up the combined organic extracts. The raw product was either in the next step without further purification used (compound 5) or by recrystallization from ether MeOH purified (compound 6).

General Procedure 2: Reaction of compounds 5 and 6 with sulfur dioxide to the corresponding SO ₂ adducts 7a / 7b and 8a / 8b (Preparations 3-6)

To a solution of crude compound 5 (or neat compound 6) (5 mmol) in dichloromethane (25 ml) and water (10 ml) was added an ice cold, about 1.5 M solution of sulfur dioxide in dichloromethane (100 ml) vigorous stirring. The mixture was stirred at ambient temperature for 45 minutes and then poured into ice-cold water (100 ml). With 2N sodium hydroxide (62 ml), the apparent pH of the mixture was adjusted to 5.6. The organic phase was separated and worked up after a further extraction of the aqueous layer (dichloromethane, 25 ml). The residue was chromatographed (5% to 10% ether in petroleum ether as eluent) to separate the 6 (S) and 6 (R) -SO ₂ adducts 7a and 7b (or 9a and 9b).

General Procedure 3: En-reaction of the SO ₂ adducts 7a, 7b, 8a, and 8b with paraformaldehyde to give the corresponding SO ₂ -protected 16-dehydroalcohols 9a, 9b, 10a, and 10b (Preparations 7-10)

To a solution Compound 7a (or 7b, 8a, 8b) (2.42 g, 4 mmol) in dichloromethane (80 ml) was added at 0 ° C with stirring Paraformaldehyde (0.60 g, 20 mmol) and then boron trifluoride etherate (0.10 ml, 0.4 equivalents). One stirred 15 minutes at 0 ° C and then quenched the reaction with 1/15 M phosphate buffer (pH 6.5) (60 ml) and the mixture worked up. The residue was chromatographed (10% to 15% ethyl acetate in petroleum ether as Eluent) to minor Quantities of the less polar starting material from the more polar title compound to separate (9a or 9b, 10a, 10b).

General Procedure 4: Deprotection of the SO ₂ adducts 9a / 9b and 10a / 10b to the corresponding 16-dehydroalcohols 11 and 12 (Preparations 11-12)

To a solution Compound 9a (or 9b) (1.27 g, 2 mmol) in toluene (20 mL) water (10 ml) and sodium bicarbonate (0.67 g, 8 mmol) and stirred the mixture for 1.5 hours at 85-90 ° C. After this cooling down At room temperature, the reaction mixture worked on (toluene), whereby the compound 11 was obtained as a foam.

A similar Treatment of Compound 10a (or 10b) provided the compound 12 as an amorphous powder.

General procedure 5: Tosylation of the 16-dehydroalcohols 11 and 12 to the corresponding Tosylates 13 and 14 (Preparations 13-14)

To a stirred solution compound 11 (or 12) (2 mmol) in pyridine (10 ml) was added at 0 ° C p-toluenesulfonyl chloride (0.76 g, 4 mmol) and stirred the mixture at 0-5 ° C for 2 hours and then left in a refrigerator overnight stand (16 hours). The reaction mixture was poured into an ice-cold Mixture of ethyl acetate (40 ml) and water and put the aqueous layer with 4 N hydrochloric acid to an apparent pH of 2.6. The aqueous phase was separated and extracted again with ethyl acetate and then worked the combined organic extracts. The residue was purified by Chromatography (5% ether in petroleum ether as eluent), whereby one received pure 13 (or 14).

General procedure 6: Oxidation of the 16-dehydroalcohols 11 and 12 to the corresponding ones Aldehydes 15 and 16 (Swern oxidation) (Preparations 15-16)

A solution of oxalyl chloride (0.45 ml, 5 mmol) in dry dichloromethane was cooled with stirring to -78 ° C and gave by means of a syringe 2 N dimethyl sulfoxide in dry dichloromethane (5.6 ml, 11.2 mmol). One stirred 10 minutes at low temperature and then gave a solution of Add 11 (or 12) (4 mmol) in dry dichloromethane (12 mL) to (syringe). One stirred another 20 minutes and then quenched the reaction by adding of triethylamine (2.1 ml, 15 mmol). The cold bath was removed and left the implementation warm to room temperature (about 45 minutes with stirring) and worked up (dichloromethane) to give the crude compound 15 (or 16) received in the next step without further Used cleaning.

General procedure 7: Alkylation of compounds 13 and 14 to compounds IIa (Preparations 17-20)

To a solution of the appropriate alkylating agent HXR ³ (1.5 mmol) in dry DMF (10 ml) was added sodium hydride (2.25 mmol) and the mixture was stirred for 20 minutes. Thereafter, a solution of Compound 13 (or 14) in dry DMF (5 ml) was added via syringe and stirred for either an additional 30-40 minutes (S-alkylation) or 16-22 hours (O-alkylation). After cooling to 0-5 ° C, excess reagent was decomposed by dropwise addition of water (0.5-1.0 ml) and the reaction mixture worked up to (ethyl acetate). The residue was purified by chromatography (5% -10% ether in petroleum ether as eluent) to give the corresponding compound IIa.

General Procedure 8: Reaction of Compounds 13 and 14 with Grignard Reagents R ⁴ MgHal, Derived from Side-Chain Building Blocks II (R ⁴ Hal), to Compounds IIb (Preparations 21-24)

To Magnesium turnings (220 mg, 1.1 atomic equivalents) in a dry flask was added dropwise with stirring and under an argon atmosphere a solution the corresponding compound VI (8.25 mmol) in dry THF (7.5 ml). After that warmed up with stirring 45 minutes at reflux. The Grignard reagent was treated with stirring at 0 ° C with a solution of Lithium chloride (32 mg) and anhydrous copper (II) chloride (50 mg) in dry THF (5 ml) and after 15 minutes with a solution of Compound 13 (or 14) in dry THF (5 ml). One touched 18 Hours at 5-10 ° C and worked then the reaction mixture on (ether). The raw product cleaned by chromatography, whereby the desired compound IIb was obtained.

General Procedure 9: Reaction of Aldehydes 15 and 16 with Ylides A ¹ R ⁵ , Derived from Side-Chain Building Block VII (AR ⁵ ), to Compounds IIc (Preparations 25-26)

To a stirred solution of the aldehyde 15 (or 16) (1.0 mmol) and the corresponding compound VII (1.8 mmol) in dry THF (5 ml) was added dropwise with a Syringe 1 M lithium bis (trimethylsilyl) amide in dry THF (1.5 ml) at -50 ° C. One stirred one for another hour at the low temperature and let it after to -10 ° C (15-20 minutes) warm up. It was quenched with a few drops of water and worked on (ether). The residue Purified by chromatography to give the desired compound IIc received.

General Procedure 10: Reaction of aldehydes 15 and 16 with ylides A ¹ R ⁶ , derived from side chain building block VIII (A ¹ R ⁶ ), to compounds IId (Preparations 27-28)

To a solution Aldehyde 15 (or 16) (1.8 mmol) in dry toluene (20 ml) gave the appropriate compound VIII (3.6 mml) and stirred the Mixture 2-4 Hours at 90-110 ° C. After this cooling down at 0 ° C the mixture was filtered and the filtrate was concentrated and purified by chromatography to give the desired compound IId.

General procedure 11: Deprotect of compounds IIb to the corresponding compounds III with PPTS (Preparations 29-32)

To a solution the corresponding compound IIb (0.5 mmol) in THF (3 ml) and ethanol (6 ml) was added PPTS (15 mg) and the mixture was stirred for one hour. Workup (ethyl acetate) gave a crude product, which was purified by chromatography to give the desired compound III.

General procedure 12: reaction of the compound IIc with alkyl lithium to the corresponding Compounds III (Preparations 33-36)

Pre-cooled (-15 ° C) alkyllithium in ether (3-4 molar equivalents) One dripped at -78 ° C with a Syringe to a stirred solution the corresponding compound IIc (0.5 mmol) in dry THF (6 ml). After a further 45 minutes at -78 ° C, the reaction was quenched with a few drops of water, warmed to 20 ° C and worked on (ether). The residue was chromatographed to give the desired compound III.

General procedure 13: Reduction of compounds IId to the corresponding compounds III (Preparations 37-40)

To a stirred solution of the corresponding compound IId (0.8 mmol) in THF (4 ml) at 0 ° C was added 0.4 M CeCl ₃ .7H ₂ O in ethanol (2 ml) and then sodium borohydride (76 mg, 2 mmol). Methanol (4 ml) was added over 10 minutes with stirring and after a further 20 minutes the mixture was worked up (ethyl acetate). The residue was purified by chromatography to give the desired compound III.

General procedure 14: Isomerization of compounds IIa and III to the corresponding Compounds IV (Preparations 41-56)

In A 25 ml Pyrex round bottom flask was irradiated with stirring solution the corresponding compound IIa or III (0.28 mmol), anthracene (0.10 g, 0.56 mmol) and triethylamine (0.20 mL, 1.4 mmol) in dichloromethane (16 ml) for 30 minutes at about 10 ° C with UV light of a TQ 760Z2 high pressure ultraviolet lamp (Hanau). The reaction mixture was evaporated under reduced pressure and treated the residue with petroleum ether (2 × 2 ml) and filtered. The filtrate was concentrated and purified Chromatography to give the title compound.

General procedure 15: Deprotect of the compounds IV to the corresponding compounds I by treatment with "HF" (Examples 1-8 and 13-16)

To a stirred solution of the corresponding compound IV (0.25 mmol) in ethyl acetate (1.5 ml) was added acetonitrile (6 ml) followed by a 5% solution of hydrofluoric acid in acetonitrile-H ₂ O 7: 1 (2.0 ml) ml). Stirring was continued for an additional 45-60 minutes, 1M potassium bicarbonate (10 mL) added and the reaction worked up to (ethyl acetate). The residue was purified by chromatography (30% pentane in ethyl acetate as eluent) to give the desired compound I.

General procedure 16: Deprotect of the compounds IV to the corresponding compounds I by treatment with tetra-n-butylammonium fluoride (Examples 9-12)

To a solution of the corresponding compound IV (0.18 mmol) in THF (4.5 ml) TBAF trihydrate (0.29 g, 0.9 mmol) and the mixture was heated for one hour with stirring at reflux. After addition of 0.2 M sodium bicarbonate (5 ml), work was carried out the mixture on (ethyl acetate). The residue was purified by Chromatography (50% ethyl acetate in pentane as eluent), to obtain the title compound.

preparations

Preparation 1: compound 5

• Procedure: General Procedure 1
• Starting material: compound 4
• ¹ H-NMR δ 0.06 (m, 12H), 0.76 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.66 (m, 3H), 1.45-2.50 (m, 13H), 2.56 (dd, 1H), 2.86 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4 , 94 (m, 1H), 4.98 (m, 1H), 5.19 (m, 1H), 5.85 (d, 1H), 6.44 (d, 1H).

Preparation 2: compound 6

• Procedure: General Procedure 1
• Starting material: compound 3
• Melting point: 87-88 ° C
• Analysis: Calculated for C ₃₃ H ₅₈ O ₂ Si ₂ : C, 73.00, H, 10.77. Found: C, 72.90, H, 10.82
• ¹ H-NMR δ 0.06 (m, 12H), 0.62 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H), 1.56 (d, 3H), 1.20-2.10 (m, 10H), 2.32 (m, 3H), 2.57 (dd, 1H), 2.89 (m, 1H), 4.22 (m, 1H), 4 , 53 (m, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.08 (m, 1H), 5.86 (d, 1H), 6.45 (d, 1H).

Preparation 3: compound 7a

• Procedure: General Procedure 2
• Starting material: compound 5
• Melting point: 117-118 ° C
• Analysis: Calculated for C ₃₃ H ₃₈ O ₄ SSi _2: C 65.29, H 9.63, S 5.28 Found: C 65.12, H 9.54, S 5.22
• ¹ H-NMR δ 0.05 (m, 12H), 0.86 (s, 9H), 0.87 (s, 9H), 0.87 (s, 3H), 1.66 (m, 3H), 1.40-2.50 (m, 14H), 2.60 (m, 1H), 3.60 (bd, 1H), 3.93 (m, 1H), 4.19 (m, 1H), 4 , 36 (m, 1H), 4.64 (d, 1H), 4.74 (d, 1H), 5.17 (m, 1H).

Preparation 4: compound 7b

• Procedure: General Procedure 2
• Starting material: compound 5
• ¹ H-NMR δ 0.06 (m, 12H), 0.78 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.66 (m, 3H), 1.45-2.45 (m, 14H), 2.56 (m, 1H), 3.63 (bd, 1H), 3.92 (bd, 1H), 4.15 (m, 1H), 4 , 38 (m, 1H), 4.62 (d, 1H), 4.84 (d, 1H), 5.19 (m, 1H).

Preparation 5: compound 8a

• Procedure: General Procedure 2
• Starting material: compound 6
• Melting point: 117-118 ° C
• Analysis: Calculated for C ₃₃ H ₅₈ O ₄ SSi ₂ : C, 65.29, H, 9.63, S, 5.28 Found: C, 65.14, H, 9.54, S, 5.08
• ¹ H-NMR δ 0.06 (m, 12H), 0.72 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.36 (m, 1H), 1.55 (d, 3H), 1.45-2.05 (m, 10H), 2.10-2.45 (m, 3H), 2.63 (m, 1H), 3.60 (bd, 1H), 3.93 (m, 1H), 4.18 (m, H), 4.36 (m, 1H), 4.65 (d, 1H), 4.75 (d, 1H), 5, 10 (m, 1H).

Preparation 6: compound 8b

• Procedure: General Procedure 2
• Starting material: compound 6
• ¹ H-NMR δ 0.06 (m, 12H), 0.64 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.55 (d, 3H), 1.20-1.95 (m, 10H), 2.08 (dd, 1H), 2.30 (m, 3H), 2.60 (m, 1H), 3.63 (bd, 1H), 3 , 92 (bd, 1H), 4.16 (m, 1H), 4.38 (m, 1H), 4.62 (d, 1H), 4.85 (d, 1H), 5.10 (m, 1H).

Preparation 7: compound 9a

• Procedure: General Procedure 3
• Starting material: Compound 7a
• Melting point: 115-116 ° C
• Analysis: Calculated for C ₃₄ H ₆₀ O ₅ SSi ₂ : C 64.10, H 9.49, S 5.03 Found: C, 63.78, H, 9.55, S, 5.00
• ¹ H-NMR δ 0.06 (m, 12H), 0.82 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.06 (d, 3H), 1.35-2.50 (m, 14H), 2.61 (m, 1H), 3.57 (m, 3H), 3.93 (m, 1H), 4.18 (m, 1H), 4 , 37 (m, 1H), 4.63 (d, 1H), 4.82 (d, 1H), 5.43 (m, 1H).

Preparation 8: compound 9b

• Procedure: General Procedure 3
• Starting material: Compound 7b
• Melting point: 131-132 ° C
• Analysis: Calculated for C ₃₄ H ₆₀ O ₅ SSi ₂ : C 64.10, H 9.49 Found: C, 64.18, H, 9.46
• ¹ H-NMR δ 0.05 (m, 12H), 0.72 (s, 3H), 0.85 (s, 9H), 0.87 (s, 9H), 1.06 (d, 3H), 1.35-2.02 (m, 9H), 2.10-2.65 (m, 6H), 3.58 (m, 3H), 3.92 (bd, 1H), 4.15 (m, 1H), 4.38 (m, 1H), 4.62 (d, 1H), 4.92 (d, 1H), 5.45 (m, 1H).

Preparation 9: compound 10a

• Procedure: General Procedure 3
• Starting material: Compound 8a
• Melting point: 125-126 ° C
• Analysis: Calculated for C ₃₄ H ₆₀ O ₅ SSi ₂ : C, 64.10, H, 9.49, H, 5.03 Found: C, 63.98, H, 9.46, S, 4.82
• ¹ H-NMR δ 0.06 (m, 12H), 0.81 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.11 (d, 3H), 1.40-2.50 (m, 14H), 2.60 (m, 1H), 3.47 (dd, 1H), 3.58 (dd, 1H), 3.60 (bd, 1H), 3 , 93 (m, 1H), 4.19 (m, 1H), 4.37 (m, 1H), 4.64 (m, 1H), 4.82 (m, 1H), 5.45 (m, 1H).

Preparation 10: compound 10b

• Procedure: General Procedure 3
• Starting material: compound 8b
• Melting point: 129-130 ° C
• ¹ H-NMR δ 0.06 (m, 12H), 0.72 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.11 (d, 3H), 1.35-2.00 (m, 9H), 2.10-2.50 (m, 5H), 2.57 (dd, 1H), 3.46 (dd, 1H), 3.59 (dd, 1H), 3.64 (bd, 1H), 3.92 (bd, 1H), 4.16 (m, 1H), 4.38 (m, 1H), 4.62 (d, 1H), 4, 93 (d, 1H), 5.48 (m, 1H).

Preparation 11: compound 11

• Procedure: General Procedure 4
• Starting material: compound 9a or 9b
• Analysis: Calculated for C ₃₄ H ₆₀ O ₃ SSi ₂ : C, 71.27, H, 10.55 Found: C, 71.00, H, 10.59
• ¹ H-NMR δ 0.05 (m, 12H), 0.71 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.06 (d, 3H), 1.35-2.00 (m, 8H), 2.09 (m, 1H), 2.28 (m, 2H), 2.41 (m, 2H), 2.58 (dd, 1H), 2 , 87 (m, 1H), 3.55 (m, 2H), 4.22 (m, 1H), 4.54 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.46 (m, 1H), 5.92 (d, 1H), 6.45 (d, 1H).

Preparation 12: compound 12

• Procedure: General Procedure 4
• Starting material: compound 10a or 10b
• ¹ H-NMR δ 0.06 (m, 1 2H), 0.70 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.11 (d, 3H) , 1.40-1.90 (m, 7H), 1.93 (m, 1H), 2.10 (m, 1H), 2.20-2.50 (m, 4H), 2.58 (d , 1H), 2.86 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 4.22 (m, 1H), 4.54 (m, 1H), 4 , 95 (m, 1H), 4.99 (m, 1H), 5.48 (m, 1H), 5.92 (d, 1H), 6.45 (d, 1H).

Preparation 13: compound 13

• Procedure: General Procedure 5
• Starting material: compound 11
• Melting point: 77-78 ° C
• Analysis: Calculated for C ₄₁ H ₆₆ O ₅ SSi ₂ : C, 67.72; H, 9.15, S, 4.41. Found: C, 67.50, H, 9.07, S, 4.67
• ¹ H-NMR δ 0.06 (m, 12H), 0.60 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H), 1.04 (d, 3H), 1.30-1.85 (m, 6H), 1.91 (m, 1H), 2.02 (m, 1H), 2.10-2.38 (m, 3H), 2.44 (s, 3H), 2.40-2.62 (m, 2H), 2.84 (m, 1H), 3.84 (t, 1H), 4.04 (dd, 1H), 4.22 (m, 1H ), 4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.31 (m, 1H), 5.88 (d, 1H), 6.43 (d, 1H), 7.33 (d, 2H), 7.78 (d, 2H).

Preparation 14: compound 14

• Procedure: General Procedure 5
• Starting material: compound 12
• Melting point: 89-90 ° C
• Analysis: Calculated for C ₄₁ H ₆₆ O ₅ SSi ₂ : C, 67.72, H, 9.15 Found: C, 67.73, H, 9.36
• ¹ H-NMR δ 0.06 (m, 12H), 0.63 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.09 (d, 3H), 2.44 (s, 3H), 2.56 (dd, 1H), 0.75-2.50 (m, 12H), 2.83 (m, 1H), 3.73 (t, 1H), 4 , 03 (dd, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.95 (m, 1H), 4.98 (m, 1H), 5.37 (m, 1H), 5.88 (d, 1H), 6.42 (d, 1H), 7.33 (d, 2H), 7.78 (d, 2H).

Preparation 15: compound 15

• Procedure: General Procedure 6
• Starting material: compound 11
• ¹ H-NMR δ 0.06 (m, 12H), 0.69 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.21 (d, 3H), 1.40-2.00 (m, 7H), 2.14 (m, 1H), 2.31 (m, 2H), 2.44 (dd, 1H), 2.58 (m, 1H), 2 , 87 (m, 1H), 3.05 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.52 (m, 1H), 5.92 (d, 1H), 6.44 (d, 1H), 9.45 (d, 1H).

Preparation 16: compound 16

• Procedure: General Procedure 6
• Starting material: compound 12
• ¹ H-NMR δ 0.06 (m, 12H), 0.70 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.24 (d, 3H), 1.00-2.00 (m, 7H), 2.14 (m, 1H), 2.29 (m, 2H), 2.46 (m, 1H), 2.57 (dd, 1H), 2 , 86 (m, 1H), 3.05 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.56 (m, 1H), 5.92 (d, 1H), 6.44 (d, 1H), 9.45 (d, 1H).

Preparation 17: compound 201

• Procedure: General Procedure 7
• Starting material: compound 13
• Alkylating agent: 3- (1-hydroxy-1-methyl) ethylphenol
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.72 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.20 (d, 3H), 1.57 (s, 6H), 1.15-2.00 (m, 8H), 2.09 (m, 1H), 2.28 (m, 2H), 2.43 (m, 1H), 2 , 60 (m, 2H), 2.87 (m, 1H), 3.81 (t, 1H), 4.00 (dd, 1H), 4.23 (m, 1H), 4.53 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.48 (m, 1H), 5.93 (d, 1H), 6.46 (d, 1H), 6, 76 (m, 1H), 7.03 (m, 2H), 7.24 (t, 1H).

Preparation 18: compound 202

• Procedure: General Procedure 7
• Starting material: compound 14
• Alkylating agent: 3- (1-hydroxy-1-methyl) ethylphenol
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.72 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.23 (d, 3H), 1.57 (s, 6H), 1.40-2.00 (m, 8H), 2.09 (m, 1H), 2.29 (m, 2H), 2.42 (m, 1H), 2 , 60 (m, 2H), 2.87 (m, 1H), 3.67 (t, 1H), 4.01 (dd, 1H), 4.23 (m, 1H), 4.54 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.51 (m, 1H), 5.93 (d, 1H), 6.46 (d, 1H), 6, 78 (m, 1H), 7.04 (m, 2H), 7.24 (t, 1H).

Preparation 19: compound 203

• Procedure: General Procedure 17
• Starting material: compound 13
• Alkylating agent: 3- (1-hydroxy-1-methyl) ethylthiophenol
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.70 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H), 1.19 (d, 3H), 1.56 (s, 6H), 1.15-1.87 (m, 7H), 1.92 (m, 1H), 2.07 (m, 1H), 2.20-2.50 (m, 4H), 2.57 (dd, 1H), 2.85 (d, 1H), 2.86 (dd, 1H), 3.20 (dd, 1H), 4.22 (m, 1H), 4, 53 (m, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.44 (m, 1H), 5.91 (d, 1H), 6.45 (d, 1H ), 7.15-7.30 (m, 3H), 7.46 (m, 1H).

Preparation 20: compound 204

• Procedure: General Procedure 7
• Starting material: compound 14
• Alkylating agent: 3- (1-hydroxy-1-methyl) ethylthiophenol
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.67 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.22 (d, 3H), 1.56 (s, 6H), 1.40-1.87 (m, 7H), 1.93 (m, 1H), 2.08 (m, 1H), 2.25 (m, 2H), 2.40 (m, 2H), 2.58 (dd, 1H), 2.79 (d , 1H), 2.84 (m, 1H), 3.18 (dd, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.95 (m, 1H), 4 , 99 (m, 1H), 5.47 (m, 1H), 5.90 (d, 1H), 6.44 (d, 1H), 7.15-7.30 (m, 3H), 7, 48 (m, 1H).

Preparation 21: compound 205

• Procedure: General Procedure 8
• Starting material: compound 13
• Alkylating agent: 4-bromo-2-methyl-2-trimethylsilyloxybutane
• As eluent in the chromatography: 1% ether in pentane
• ¹ H-NMR δ 0.07 (m, 21H), 0.68 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.02 (d, 3H), 1.18 (s, 6H), 1.10-2.45 (m, 18H), 2.60 (dd, 1H), 2.85 (m, 1H), 4.22 (m, 1H), 4 , 53 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.30 (m, 1H), 5.92 (d, 1H), 6.46 (d, 1H).

Preparation 22: compound 206

• Procedure: General Procedure 8
• Starting material: compound 14
• Alkylating agent: 4-bromo-2-methyl-2-trimethylsilyloxybutane
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.10 (s, 9H), 0.69 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 1.05 (d, 3H), 1.19 (s, 6H), 1.10-2.45 (m, 18H), 2.59 (dd, 1H), 2.85 (m, 1H), 4 , 22 (m, 1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.33 (m, 1H), 5.92 (d, 1H), 6,46 (d, 1H).

Preparation 23: compound 207

• Procedure: General Procedure 8
• Starting material: compound 13
• Alkylating agent: 6-bromo-2-ethyl-3-trimethylsilyloxyhexane
• As eluent in the chromatography: 1% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.08 (s, 9H), 0.68 (s, 3H), 0.80 (t, 6H), 0.85 (s, 9H), 0.90 (s, 9H), 1.01 (d, 3H), 1.44 (q, 4H), 0.75-2.45 (m, 20H), 2.58 (dd, 1H), 2 , 85 (m, 1H), 4.22 (m, 1H), 4.54 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.30 (m, 1H), 5.92 (d, 1H), 6.46 (d, 1H).

Preparation 24: compound 208

• Procedure: General Procedure 8
• Starting material: compound 14
• Alkylating agent: 6-bromo-3-ethyl-3-trimethylsilyloxyhexane
• As eluent in the chromatography: 1% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.08 (s, 9H), 0.69 (s, 3H), 0.80 (t, 6H), 0.85 (s, 9H), 0.90 (s, 9H), 1.04 (d, 3H), 1.15-2.45 (m, 20H), 1.44 (q, 4H), 2.59 (dd, 1H), 2 , 86 (m, 1H), 4.22 (m, 1H), 4.54 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.32 (m, 1H), 5.92 (d, 1H), 6.46 (d, 1H).

Preparation 25: compound 209

• Procedure: General Procedure 9
• Starting material: compound 15
• As eluent in the chromatography: 2.5% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.65 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.19 (d, 3H), 1.15-1.87 (m, 6H), 1.93 (m, 1H), 2.06 (m, 1H), 2.25 (m, 2H), 2.38 (dd, 1H), 2 , 58 (dd, 1H), 2.84 (m, 1H), 3.00 (m, 1H), 3.73 (s, 3H), 4.22 (m, 1H), 4.52 (m, 1H), 4.95 (m, 1H), 4.98 (m, 1H), 5.41 (m, 1H), 5.81 (d, 1H, J = 15.4 Hz), 5.90 ( d, 1H), 6.03 (dd, 1H, J = 15.2 Hz and 7.8 Hz), 6.16 (dd, 1H, J = 15.2 Hz and 10.5 Hz), 6.44 (d, 1H), 7.27 (dd, 1H, J = 15.4 Hz and 10.5 Hz).

Preparation 26: compound 210

• Procedure: General Procedure 9
• Starting material: compound 16
• As eluent in the chromatography: 2.5% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.69 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.20 (d, 3H), 1.35-1.87 (m, 6H), 1.93 (m, 1H), 2.07 (m, 1H), 2.25 (m, 2H), 2.41 (dd, 1H), 2 , 58 (dd, 1H), 2.84 (bd, 1H), 2.98 (m, 1H), 3.73 (s, 3H), 4.22 (m, 1H), 4.54 (m, 1H), 4.95 (m, 1H), 4.98 (m, 1H), 5.41 (m, 1H), 5.80 (d, 1H, J = 15.4Hz), 5.91 ( d, 1H), 6.11 (m, 2H), 6.44 (d, 1H), 7.27 (dd, 1H, J = 15.4 Hz and 9.9 Hz),

Preparation 27: compound 213

• Procedure: General Procedure 10
• Starting material: compound 15
• As eluent in the chromatography: 2.5% ether in petroleum ether
• ¹ H-NMR δ 0.05 (m, 12H), 0.67 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 0.80-0.95 (m , 2H), 1.07 (m, 2H), 1.22 (d, 3H), 1.45-2.35 (m, 11H), 2.41 (dd, 1H), 2.58 (dd, 1H), 2.85 (m, 1H), 3.06 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.95 (m, 1H), 4, 98 (m, 1H), 5.44 (m, 1H), 5.90 (d, 1H), 6.20 (dd, 1H, J = 1.0 and 15.8 Hz), 6.44 (i.e. , 1H), 6.82 (dd, 1H, J = 7.9 and 15.8 Hz).

Preparation 28: compound 214

• Procedure: General Procedure 10
• Starting material: compound 16
• As eluent in the chromatography: 2.5% ether in petroleum ether
• ¹ H-NMR δ 0.05 (m, 12H), 0.70 (s, 3H), 0.85 (s, 9H), 0.90 (s, 9H), 0.82-0.95 (m , 2H), 1.07 (m, 2H), 1.24 (d, 3H), 1.35-2.50 (m, 12H), 2.58 (dd, 1H), 2.84 (bd, 1H), 3.04 (m, 1H), 4.22 (m, 1H), 4.53 (m, 1H), 4.95 (m, 1H), 4.98 (m, 1H), 5, 46 (m, 1H), 5.91 (d, 1H), 6.18 (dd, 1H, J = 1.0 and 15.8 Hz), 6.44 (d, 1H), 6.85 (dd , 1H, J = 7.7 and 15.8 Hz).

Preparation 29: compound 305

• Procedure: General Procedure 11
• Starting material: compound 205
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.68 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.02 (d, 3H), 1.19 (s, 6H), 1.10-2.45 (m, 19H), 2.58 (dd, 1H), 2.85 (m, 1H), 4.22 (m, 1H), 4 , 53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.31 (m, 1H), 5.92 (d, 1H), 6.45 (d, 1H).

Preparation 30: compound 306

• Procedure: General Procedure 11
• Starting material: compound 206
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.69 (s, 3H), 0.85 (s, 9H), 0.89 (s, 9H), 1.05 (d, 3H), 1.20 (s, 6H), 1.10-2.45 (m, 19H), 2.58 (dd, 1H), 2.85 (m, 1H), 4.22 (m, 1H), 4 , 54 (m, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.33 (m, 1H), 5.91 (d, 1H), 6.45 (d, 1H).

Preparation 31: compound 307

• Procedure: General Procedure 11
• Starting material: compound 207
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.67 (s, 3H), 0.84 (t, 6H), 0.85 (s, 9H), 0.90 (s, 9H), 1.01 (d, 3H), 1.44 (q, 4H), 0.80-2.45 (m, 21H), 2.58 (dd, 1H), 2.85 (m, 1H), 4 , 22 (m, 1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.29 (m, 1H), 5.91 (d, 1H), 6.45 (d, 1H).

Preparation 32: compound 308

• Procedure: General Procedure 11
• Starting material: compound 208
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.68 (s, 3H), 0.85 (s, 6H), 0.85 (t, 9H), 0.90 (s, 9H), 1.04 (d, 3H), 1.45 (q, 4H), 1.15-2.45 (m, 21H), 2.59 (dd, 1H), 2.86 (m, 1H), 4 , 22 (m, 1H), 4.54 (m, 1H), 4.94 (m, 1H), 4.99 (m, 1H), 5.32 (m, 1H), 5.91 (d, 1H), 6,46 (d, 1H).

Preparation 33: compound 309

• Procedure: General Procedure 12
• Starting material: compound 209
• Organometallic reagent: methyllithium
• As eluent in the chromatography: 5% ether in petroleum ether

Preparation 34: compound 310

• Procedure: General Procedure 12
• Starting material: compound 210
• Organometallic reagent: methyllithium
• As eluent in the chromatography: 2.5% ether in petroleum ether

Preparation 35: compound 311

• Procedure: General Procedure 12
• Starting material: compound 209
• Organometallic reagent: ethyllithium
• As eluent in the chromatography: 5% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.67 (s, 3H), 0.85 (t, 6H), 0.85 (s, 9H), 0.89 (s, 9H), 1.16 (d, 3H), 1.10-1.87 (m, 1H), 1.92 (m, 1H), 2.04 (m, 1H), 2.25 (m, 2H), 2 , 38 (dd, 1H), 2.59 (dd, 1H), 2.89 (m, 2H), 4.22 (m, 1H), 4.53 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.38 (m, 1H), 5.54 (d, 1H, J = 15.3Hz), 5.59 (dd, 1H, J = 14.9 Hz and 8.0 Hz), 5.90 (d, 1H), 6.02 (dd, 1H, J = 14.9 Hz and 10.3 Hz), 6.17 (dd, 1H, J = 15, 3 Hz and 10.3 Hz), 6.45 (d, 1H).

Preparation 36: compound 312

• Procedure: General Procedure 12
• Starting material: compound 210
• Organometallic reagent: ethyllithium
• As eluent in the chromatography: 5% ether in pentane
• 0.06 (m, 12H), 0.69 (s, 3H), 0.85 (s, 9H), 0.86 (t, 6H), 0.90 (s, 9H), 1.17 (d, 3H), 1.25-1.87 (m, 11H), 1.93 (m, 1H), 2.05 (m, 1H), 2.26 (m, 2H), 2.42 (dd, 1H), 2.59 (dd, 1H), 2.86 (m, 2H), 4.22 (m, 1H), 4.54 (m, 1H), 4.95 (m, 1H), 4.99 (m, 1H), 5.38 (m, 1H), 5.54 (d, 1H, J = 15.3 Hz), 5.64 (dd, 1H, J = 15.0 Hz and 7.7 Hz), 5.91 (d, 1H), 6.01 (dd, 1H, J = 15.0 Hz and 10.3 Hz), 6.18 (dd, 1H, J = 15.3 Hz and 10.3 Hz), 6.45 (d, 1H).

Preparation 37: compound 313

• Procedure: General Procedure 13
• Starting material: compound 213
• As eluent in the chromatography: 10% ether in petroleum ether
• ¹ H-NMR δ 0.05 (m, 12H), 0.22 (m, 1H), 0.32 (m, 1H), 0.49 (m, 2H), 0.68 (s, 3H), 0.85 (s, 9H), 0.86 (s, 9H), 0.97 (s, 1H), 1.15 (d, 3H), 1.40-2.10 (m, 9H), 2 , 15-2.45 (m, 3H), 2.58 (dd, 1H), 2.87 (m, 2H), 3.42 (m, 1H), 4.22 (m, 1H), 4, 53 (m, 1H), 4.94 (m, 1H), 5.00 (m, 1H), 5.37 (m, 1H), 5.54 (m, 2H), 5.90 (d, 1H ), 6.44 (d, 1H).

Preparation 38: compound 314

• Procedure: General Procedure 13
• Starting material: compound 214
• As eluent in the chromatography: 10% ether in petroleum ether.

Preparation 39: compound 315

• Procedure: General Procedure 13
• Starting material: compound 213
• As eluent in the chromatography: 10% ether in petroleum ether.
• ¹ H-NMR δ 0.05 (m, 12H), 0.23 (m, 1H), 0.32 (m, 1H), 0.51 (m, 2H), 0.68 (s, 3H), 0.85 (s, 6H), 0.90 (s, 9H), 0.98 (m, 9H), 1.15 (d, 3H), 1.45-2.10 (m, 9H), 2 , 17-2.45 (m, 3H), 2.58 (dd, 1H), 2.87 (m, 2H), 3.46 (m, 1H), 4.22 (m, 1H), 4, 54 (m, 1H), 4.94 (m, 1H), 4.98 (m, 1H), 5.37 (m, 1H), 5.58 (m, 2H), 5.90 (d, 1H ), 6.45 (d, 1H).

Preparation 40: compound 316

• Procedure: General Procedure 13
• Starting material: compound 214
• As eluent in the chromatography: 10% ether in petroleum ether.

Preparation 41: compound 401

• Procedure: General Procedure 14
• Starting material: compound 201
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.71 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 1.19 (d, 3H), 1.56 (s, 6H), 1.15-2.70 (m, 14H), 2.82 (m, 1H), 3.80 (t, 1H), 4.00 (dd, 1H), 4 , 19 (m, 1H), 4.37 (m, 1H), 4.87 (m, 1H), 5.18 (m, 1H), 5.45 (m, 1H), 6.10 (d, 1H), 6.23 (d, 1H), 6.77 (m, 1H), 7.03 (m, 2H), 7.23 (t, 1H).

Preparation 42: compound 402

• Procedure: General Procedure 14
• Starting material: compound 202
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.71 (s, 3H), 0.87 (s, 18H), 1.22 (d, 3H), 1.57 (s, 6H), 1.40-2.15 (m, 9H), 2.23 (m, 2H), 2.37 (m, 1H), 2.45 (dd, 1H), 2.61 (m, 1H), 2 , 82 (m, 1H), 3.66 (t, 1H), 4.01 (dd, 1H), 4.19 (m, 1H), 4.38 (m, 1H), 4.88 (m, 1H), 5.18 (m, 1H), 5.48 (m, 1H), 6.11 (d, 1H), 6.23 (d, 1H), 6.77 (m, 1H), 6, 95-7.10 (m, 2H), 7.24 (t, 1H).

Preparation 43: compound 403

• Procedure: General Procedure 14
• Starting material: compound 203
• As eluent in the chromatography: 10% ether in pentane.
• ¹ H-NMR δ 0.06 (m, 12H), 0.69 (s, 3H), 0.87 (s, 18H), 1.18 (d, 3H), 1.55 (s, 6H), 1.15-2.50 (m, 14H), 2.80 (m, 1H), 2.86 (dd, 1H), 3.20 (dd, 1H), 4.18 (m, 1H), 4 , 38 (m, 1H), 4.87 (m, 1H), 5.19 (m, 1H), 5.41 (m, 1H), 6.09 (d, 1H), 6.22 (d, 1H), 7.15-7.30 (m, 3H), 7.46 (m, 1H).

Preparation 44: compound 404

• Procedure: General Procedure 14
• Starting material: compound 204
• As eluent in the chromatography: 10% ether in pentane.
• ¹ H-NMR δ 0.05 (m, 12H), 0.66 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 1.21 (d, 3H), 1.56 (s, 6H), 1.30-2.50 (m, 14H), 2.78 (dd, 1H), 2.80 (m, 1H), 3.18 (dd, 1H), 4 , 18 (m, 1H), 4.37 (m, 1H), 4.86 (m, 1H), 5.18 (m, 1H), 5.44 (m, 1H), 6.08 (d, 1H), 6.22 (d, 1H), 7.15-7.30 (m, 3H), 7.47 (m, 1H).

Preparation 45: compound 405

• Procedure: General Procedure 14
• Starting material: compound 305
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.67 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.01 (d, 3H), 1.18 (s, 6H), 0.80-2.27 (m, 18H), 2.35 (m, 1H), 2.45 (dd, 1H), 2.80 (m, 1H), 4 , 19 (m, 1H), 4.37 (m, 1H), 4.87 (m, 1H), 5.18 (m, 1H), 5.28 (m, 1H), 6.09 (d, 1H), 6.23 (d, 1H).

Preparation 46: compound 406

• Procedure: General Procedure 14
• Starting material: compound 306
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.68 (s, 3H), 0.87 (s, 9H), 0.88 (s, 9H), 1.04 (d, 3H), 1.20 (s, 6H), 1.10-2.40 (m, 19H), 2.45 (d, 1H), 2.80 (m, 1H), 4.18 (m, 1H), 4 , 38 (m, 1H), 4.87 (m, 1H), 5.18 (m, 1H), 5.30 (m, 1H), 6.10 (d, 1H), 6.23 (d, 1H).

Preparation 47: compound 407

• Procedure: General Procedure 14
• Starting material: compound 307
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.66 (s, 3H), 0.84 (t, 6H), 0.87 (s, 18H), 1.00 (d, 3H), 1.44 (q, 4H), 0.75-2.27 (m, 20H), 2.34 (m, 1H), 2.44 (dd, 1H), 2.80 (m, 1H), 4 , 19 (m, 1H), 4.38 (m, 1H), 4.87 (m, 1H), 5.18 (m, 1H), 5.27 (m, 1H), 6.09 (d, 1H), 6,22 (d, 1H).

Preparation 48: compound 408

• Procedure: General Procedure 14
• Starting material: compound 308
• As eluent in the chromatography: 10% ether in pentane
• ¹ H-NMR δ 0.06 (m, 12H), 0.68 (s, 3H), 0.87 (t, 6H), 0.87 (s, 9H), 0.88 (s, 9H), 1.02 (d, 3H), 1.44 (q, 4H), 1.15-2.50 (m, 22H), 2.80 (m, 1H), 4.19 (m, 1H), 4 , 38 (m, 1H), 4.87 (m, 1H), 5.18 (m, 1H), 5.29 (m, 1H), 6.09 (d, 1H), 6.23 (d, 1H).

Preparation 49: compound 409

• Procedure: General Procedure 14
• Starting material: compound 309
• As eluent in the chromatography: 5% ether in petroleum ether

Preparation 50: compound 410

• Procedure: General Procedure 14
• Starting material: compound 310
• As eluent in the chromatography: 5% ether in petroleum ether

Preparation 51: compound 411

• Procedure: General Procedure 14
• Starting material: compound 311
• As eluent in the chromatography: 5% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.66 (s, 3H), 0.85 (t, 6H), 0.85 (s, 9H), 0.86 (s, 9H), 1.15 (d, 3H), 1.10-1.92 (m, 12H), 1.99 (m, 1H), 2.18 (m, 2H), 2.33 (dd, 1H), 2 , 45 (dd, 1H), 2.77 (dd, 1H), 2.90 (m, 1H), 4.18 (m, 1H), 4.37 (m, 1H), 4.87 (m, 1H), 5.17 (m, 1H), 5.35 (m, 1H), 5.53 (d, 1H, J = 15.3Hz), 5.58 (dd, 1H, J = 14.9 Hz and 8.0 Hz), 5.95-6.27 (m, 4H).

Preparation 52: compound 412

• Procedure: General Procedure 14
• Starting material: compound 312
• As eluent in the chromatography: 5% ether in pentane
• ¹ H-NMR δ 0.05 (m, 12H), 0.68 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 0.83-0.95 (t , 6H), 1.16 (d, 3H), 1.10-2.30 (m, 15H), 2.36 (dd, 1H), 2.44 (dd, 1H), 2.79 (m, 1H), 2.88 (m, 1H), 4.18 (m, 1H), 4.37 (m, 1H), 4.87 (m, 1H), 5.17 (m, 1H), 5, 35 (m, 1H), 5.53 (d, 1H, J = 15.4 Hz), 5.64 (dd, 1H, J = 7.7 and 15.0 Hz), 5.92-6.25 (m, 4H).

Preparation 53: compound 413

• Procedure: General Procedure 14
• Starting material: compound 313
• As eluent in the chromatography: 10% ether in petroleum ether
• ¹ H-NMR δ 0.05 (m, 12H), 0.23 (m, 1H), 0.31 (m, 1H), 0.50 (m, 2H), 0.67 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 0.97 (s, 1H), 1.14 (d, 3H), 1.30-2.07 (m, 9H), 2 , 20 (m, 2H), 2.32 (m, 1H), 2.44 (dd, 1H), 2.79 (m, 1H), 2.89 (m, 1H), 3.42 (m, 1H), 4.19 (m, 1H), 4.37 (m, 1H), 4.87 (m, 1H), 5.17 (m, 1H), 5.35 (m, 1H), 5, 54 (m, 2H), 6.08 (d, 1H), 6.22 (d, 1H).

Preparation 54: compound 414

• Procedure: General Procedure 14
• Starting material: compound 314
• As eluent in the chromatography: 10% ether in petroleum ether

Preparation 55: compound 415

• Procedure: General Procedure 14
• Starting material: compound 315
• As eluent in the chromatography: 10% ether in petroleum ether
• ¹ H NMR δ 0.05 (m, 12H), 0.23 (m, 1H), 0.31 (m, 1H), 0.50 (m, 2H), 0.67 (s, 3H), 0 , 86 (s, 9H), 0.87 (s, 9H), 1.14 (d, 3H), 0.90-2.05 (m, 10H), 2.19 (m, 2H), 2, 33 (m, 1H), 2.44 (dd, 1H), 2.79 (m, 1H), 2.89 (m, 1H), 3.46 (m, 1H), 4.18 (m, 1H ), 4.36 (m, 1H), 4.87 (m, 1H), 5.17 (m, 1H), 5.34 (m, 1H), 5.57 (m, 2H), 6.08 (d, 1H), 6,22 (d, 1H).

Preparation 56: compound 416

• Procedure: General Procedure 14
• Starting material: compound 316
• As eluent in the chromatography: 10% ether in petroleum ether

Examples

Example 1: 1 (S), 3 (R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-methylethyl) phenoxymethyl) -9,10-secopregna-5 (Z), 7 (E) , 10 (19), 16-tetraene (Compound 101)

• Procedure: General Procedure 15
• Starting material: compound 401
• As eluent in the chromatography: 30% pentane in ethyl acetate.
• ¹ H NMR δ 0.73 (s, 3H), 1.20 (d, 3H), 1.57 (s, 6H), 1.15-1.97 (m, 9H), 2.04 (m , 2H), 2.17-2.45 (m, 3H), 2.60 (m, 2H), 2.83 (dd, 1H), 3.81 (t, 1H), 4.00 (dd, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.01 (m, 1H), 5.33 (m, 1H), 5.45 (m, 1H), 6, 12 (d, 1H), 6.37 (d, 1H), 6.77 (m, 1H), 7.04 (m, 2H), 7.24 (t, 1H).

Example 2: 1 (S), 3 (R) -dihydroxy-20 (R) - (3- (1-hydroxy-1-methylethyl) phenoxymethyl) -9,10-secopregna-5 (Z), 7 (E) , 10 (19), 16-tetraene (Compound 102)

• Procedure: General Procedure 15
• Starting material: compound 402
• As eluent in the chromatography: 30% pentane in ethyl acetate,
• ¹ H NMR δ 0.73 (s, 3H), 1.23 (d, 3H), 1.57 (s, 6H), 1.45-1.97 (m, 9H), 2.05 (m , 2H), 2.15-2.45 (m, 3H), 2.60 (m, 2H), 2.83 (m, 1H), 3.67 (t, 1H), 4.00 (dd, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.02 (m, 1H), 5.34 (m, 1H), 5.49 (m, 1H), 6, 12 (d, 1H), 6.37 (d, 1H), 6.77 (m, 1H), 7.04 (m, 2H), 7.24 (t, 1H).

Example 3: 1 (S), 3 (R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-methylethyl) phenylthiomethyl) -9,10-secopregna-5 (Z), 7 (E) , 10 (19), 16-tetraene (Connection 103)

• Procedure: General Procedure 15
• Starting material: compound 403
• As eluent in the chromatography: 30% pentane in ethyl acetate.
• ¹ H-NMR δ 0.71 (s, 3H), 1.19 (d, 3H), 1.56 (s, 6H), 1.15-2.50 (m, 15H), 2.58 (dd , 1H), 2.81 (dd, 1H), 2.87 (dd, 1H), 3.19 (dd, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5 , 00 (m, 1H), 5.33 (m, 1H), 5.42 (m, 1H), 6.11 (d, 1H), 6.36 (d, 1H), 7.15-7, 30 (m, 3H), 7.46 (m, 1H).

Example 4: 1 (S), 3 (R) -dihydroxy-20 (R) - (3- (1-hydroxy-1-methylethyl) phenylthiomethyl) -9,10-secopregna-5 (Z), 7 (E) , 10 (19), 16-tetraene (Connection 104)

• Procedure: General Procedure 15
• Starting material: compound 404
• As eluent in the chromatography: 30% pentane in ethyl acetate.
• ¹ H-NMR δ 0.68 (s, 3H), 1.22 (d, 3H), 1.57 (s, 6H), 1.30-2.50 (m, 15H), 2.60 (dd , 1H), 2.80 (dd, 1H), 2.82 (m, 1H), 3.18 (dd, 1H), 4.23 (m, 1H), 4.44 (m, 1H), 5 , 00 (m, 1H), 5.33 (m, 1H), 5.46 (m, 1H), 6.10 (d, 1H), 6.36 (d, 1H), 7.15-7, 30 (m, 3H), 7.48 (m, 1H).

Example 5: 1 (S), 3 (R) -dihydroxy-20 (R) - (4-hydroxy-4-methylpent-1-yl) -9,10-secopregna-5 (Z), 7 (E) 10 (19), 16-tetraene (Compound 105)

• Procedure: General Procedure 15
• Starting material: compound 405
• As eluent in the chromatography: 40% pentane in ethyl acetate.
• ¹ H-NMR δ 0.69 (s, 3H), 1.02 (d, 3H), 1.19 (s, 6H), 0.80-2.40 (m, 21H), 2.60 (dd , 1H), 2.82 (m, 1H), 4.22 (m, 1H), 4.44 (m, 1H), 5.02 (m, 1H), 5.29 (m, 1H), 5 , 34 (m, 1H), 6,11 (d, 1H), 6,38 (d, 1H).

Example 6: 1 (S), 3 (R) -dihydroxy-20 (S) - (4-hydroxy-4-methylpent-1-yl) -9,10-secopregna-5 (Z), 7 (E), 10 (19), 16-tetraene (Compound 106)

• Procedure: General Procedure 15
• Starting material: compound 406
• As eluent in the chromatography: 30% pentane in ethyl acetate.
• ¹ H NMR δ 0.70 (s, 3H), 1.05 (d, 3H), 1.21 (s, 6H), 1.15-2.40 (m, 21H), 2.60 (m , 1H), 2.82 (m, 1H), 4.24 (m, 1H), 4.42 (m, 1H), 5.01 (m, 1H), 5.33 (m, 2H), 6 , 10 (d, 1H), 6.37 (d, 1H).

Example 7: 1 (S), 3 (R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxyhept-1-yl) -9,10-secopregna-5 (Z), 7 (E) 10 (19), 16-tetraene (Compound 107)

• Procedure: General Procedure 15
• Starting material: compound 407
• As eluent in the chromatography: 40% pentane in ethyl acetate.
• ¹ H-NMR δ 0.68 (s, 3H), 0.85 (t, 6H), 1.01 (d, 3H), 1.45 (q, 4H), 0.80-2.45 (m , 23H), 2.60 (m, 1H), 2.82 (m, 1H), 4.23 (m, 1H), 4.44 (m, 1H), 5.02 (m, 1H), 5 , 28 (m, 1H), 5.34 (m, 1H), 6.11 (d, 1H), 6.38 (d, 1H).

Example 8: 1 (S), 3 (R) -dihydroxy-20 (S) - (5-ethyl-5-hydroxyhept-1-yl) -9,10-secopregna-5 (Z), 7 (E) 10 (19), 16-tetraene (Compound 108)

• Procedure: General Procedure 15
• Starting material: compound 408
• As eluent in the chromatography: 40% pentane in ethyl acetate.
• ¹ H NMR δ 0.70 (s, 3H), 0.85 (t, 6H), 1.03 (d, 3H), 1.45 (q, 4H), 1.00-2.40 (m , 23H), 2.60 (dd, 1H), 2.81 (m, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.01 (m, 1H), 5 , 31 (m, 1H), 5.33 (m, 1H), 6.11 (d, 1H), 6.37 (d, 1H).

Example 9: 1 (S), 3 (R) -dihydroxy-20 (R) - (5-hydroxy-5-methylhexa-1 (E), 3 (E) -dien-1-yl) -9,10- secopregna-5 (Z), 7 (E), 10 (19), 16-tetraene (compound 109)

• Procedure: General Procedure 16
• Starting material: compound 409

Example 10: 1 (S), 3 (R) -dihydroxy-20 (S) - (5-hydroxy-5-methylhexa-1 (E), 3 (E) -dien-1-yl) -9,10- secopregna-5 (Z), 7 (E), 10 (19), 16-tetraene (compound 110)

• Procedure: General Procedure 15
• Starting material: compound 410

Example 11: 1 (S), 3 (R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxyhepta-1 (E), 3 (E) -dien-1-yl) -9,10- secopregna-5 (Z), 7 (E), 10 (19), 16-tetraene (compound 111)

• Procedure: General Procedure 16
• Starting material: compound 411
• ¹ H-NMR δ 0.68 (s, 3H), 0.86 (t, 6H), 1.16 (d, 3H), 1.56 (q, 4H), 1.35-2.43 (m , 14H), 2.59 (dd, 1H), 2.80 (dd, 1H), 2.91 (m, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5 , 00 (m, 1H), 5.33 (m, 1H), 5.37 (m, 1H), 5.55 (d, 1H, J = 15.4 Hz), 5.58 (dd, 1H, J = 14.9 Hz and 8.0 Hz), 5.95-6.25 (m, 3H), 6.36 (d, 1H).

Example 12: 1 (S), 3 (R) -dihydroxy-20 (S) - (5-ethyl-5-hydroxyhepta-1 (E), 3 (E) -dien-1-yl) -9,10- secopregna-5 (Z), 7 (E), 10 (19), 16-tetraene (compound 112)

• Procedure: General Procedure 16
• Starting material: compound 412
• ¹ H-NMR δ 0.71 (s, 3H), 0.86 (t, 6H), 1.17 (d, 3H), 0.83-2.45 (m, 18H), 2.60 (dd , 1H), 2.80 (m, 1H), 2.89 (m, 1H), 4.23 (m, 1H), 4.44 (m, 1H), 5.01 (m, 1H), 5 , 33 (m, 1H), 5.37 (m, 1H), 5.55 (d, 1H, J = 15.3 Hz), 5.64 (dd, 1H, J = 7.7 and 15.0 Hz), 6.01 (dd, 1H, J = 10.3 and 15.0 Hz), 6.11 (d, 1H), 6.18 (dd, 1H, J = 10.3 and 15.3 Hz ), 6.37 (d, 1H).

Example 13: 1 (S), 3 (R) -dihydroxy-20 (R) - (3-cyclopropyl-3-hydroxyprop-1 (E) -en-1-yl) -9,10-secopregna-5 (Z ), 7 (e), 10 (19), 16-tetraene (24 (S) isomer) (compound 113)

• Procedure: General Procedure 16
• Starting material: compound 413
• ¹ H-NMR δ 0.23 (m, 1H), 0.32 (m, 1H), 0.51 (m, 2H), 0.70 (s, 3H), 0.99 (m, 1H), 1.15 (d, 3H), 1.10-2.40 (m, 14H), 2.59 (dd, 1H), 2.80 (dd, 1H), 2.90 (m, 1H), 3 , 42 (m, 1H), 4.23 (m, 1H), 4.43 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 5.37 (m, 1H), 5.55 (m, 2H), 6.10 (d, 1H), 6.36 (d, 1H).

Example 14: 1 (S), 3 (R) -dihydroxy-20 (S) - (3-cyclopropyl-3-hydroxyprop-1 (E) -en-1-yl) -9,10-secopregna-5 (Z ), 7 (e), 10 (19), 16-tetraene (24 (S) isomer) (compound 114)

• Procedure: General Procedure 16
• Starting material: compound 414

Example 15: 1 (S), 3 (R) -dihydroxy-20 (R) - (3-cyclopropyl-3-hydroxyprop-1 (E) -en-1-yl) -9,10-secopregna-5 (Z ), 7 (e), 10 (19), 16-tetraene (24 (R) isomer) (compound 115)

• Procedure: General Procedure 16
• Starting material: compound 415
• ¹ H-NMR δ 0.23 (m, 1H), 0.32 (m, 1H), 0.51 (m, 2H), 0.70 (s, 3H), 0.99 (m, 1H), 1.15 (d, 3H), 1.12-2.45 (m, 14H), 2.60 (bd, 1H), 2.80 (m, 1H), 2.90 (m, 1H), 3 , 46 (m, 1H), 4.23 (m, 1H), 4.44 (m, 1H), 5.00 (m, 1H), 5.33 (m, 1H), 5.36 (m, 1H), 5.58 (m, 2H), 6.10 (d, 1H), 6.36 (d, 1H).

Example 16: 1 (S), 3 (R) -dihydroxy-20 (S) - (3-cyclopropyl-3-hydroxyprop-1 (E) -en-1-yl) -9,10-secopregna-5 (Z ), 7 (e), 10 (19), 16-tetraene (24 (R) isomer) (compound 116)

• Procedure: General Procedure 16
• Starting material: compound 416

Example 17: Capsules with a content of compound III

you solved the Compound 111 in peanut oil in a final concentration of 1 μg Compound 111 / ml oil. you mixed 10 parts by weight of gelatin, 5 parts by weight of glycerol, 0.08 parts by weight Potassium sorbate and 14 parts by weight of distilled water with heating and shaped soft gelatin capsules. These were filled with 100 .mu.l of the compound 111 in oily Solution, so each capsule 0.1 μg Compound III contained.

Example 18: Dermatological Cream containing compound 111

In 1 g almond oil you solved 0.05 mg of compound III. To this solution was added 40 g of mineral oil and 20 g self-emulsifying beeswax. The mixture was heated to liquefaction. After the addition of 40 ml of hot Water was mixed thoroughly the mixture. The obtained cream contains about 0.5 μg Compound 111 per gram of cream.

Claims (9)

Compound of formula I

wherein Q is methylene, ethylene, tri-, tetra- or pentamethylene, -CH = CH-, -CH = CH-CH = CH-, -CH = CH-C≡C-, -CH = CH-CH ₂ -, -C≡C, -C≡C-CH ₂ -, -CH (R) - (CH ₂ ) ₂ -, -CH (R) -CH = CH- or -CH (R) -C≡C- wherein R is C ₁ -C ₃ alkyl; Y is either a single bond, a carbonyl group or a divalent methylene radical, ethylene radical, -CH (OH) radical, -O- (C ₆ H ₄ ) radical (ortho, meta, para) or -S- ( C ₆ H ₄ ) radical (ortho, meta, para); R ¹ and R ² , which may be the same or different, are hydrogen or a C ₁ -C ₆ hydrocarbon radical; or R ¹ and R ² together with the carbon atom bearing the group Z (marked with * in formula I) can form a C ₃ -C ₆ -carbocyclic ring; and Z is hydrogen or hydroxy; with the proviso that the configuration at C-20 can not be R if Q is ethylene, Y is methylene, carbonyl or -CH (OH) -, R ¹ and R ^{2 are} methyl and Z is hydroxy. Diastereomer of a compound according to claim 1 in pure form; or a mixture of diastereomers of a compound according to claim 1. A compound according to claim 1, namely: a) 1 (S), 3 (R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-methylethyl) phenoxy-methyl) -9,10-secopregna-5 (Z), 7 (E. ), 10 (19), 16-tetraene or the corresponding 20 (R) isomer, b) 1 (S), 3 (R) -dihydroxy-20 (S) - (3- (1-hydroxy-1-methylethyl) phenylthiomethyl) -9,10-secopregna-5 (Z), 7 (E. ), 10 (19), 16-tetraene or the corresponding 20 (R) isomer, c) 1 (S), 3 (R) -dihydroxy-20 (S) - (4-hydroxy-4-methylpent-1-yl) -9,10-secopregna-5 (Z), 7 (E), 10 (19), 16-tetraene, d) 1 (S), 3 (R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxyhept-1-yl) -9,10-secopregna-5 (Z), 7 (E), 10 (19 ), 16-tetraene or the corresponding 20 (S) isomer, e) 1 (S), 3 (R) -dihydroxy-20 (R) - (5-ethyl-5-hydroxyhept-1 (E), 3 (E) -dien-1-yl) -9,10-secopregna -5 (Z), 7 (e), 10 (19), 16-tetraene or the corresponding 20 (S) isomer, f) 1 (S), 3 (R) -dihydroxy-20 (R) - (3-cyclopropyl-3-hydroxyprop-1 (E) -en-1-yl) -9,10-secopregna-5 (Z) , 7 (e), 10 (19), 16-tetraene (24 (S) isomer) or the corresponding 24 (R) isomer. A process for the preparation of a compound of formula I according to claim 1, wherein: a) the side chain attached to C-20 in compound I from the 20 (S) and 20 (R) isomers of 1 (S), 3 (R ) -Bis (tert-butyldimethylsilyloxy) -20-p-toluenesulfonyloxymethyl-9,10-secopregna-5 (E), 7 (E), 10 (19), 16-tetraene, either (i) by reaction with a side chain building block HXR ³ (X is O or S, R ³ is -C ₆ H ₄ -CR ¹ R ² Z ¹ (meta) and Z ¹ is hydroxy or protected hydroxy) in the presence of a base (eg NaH) in a solvent (eg DMF), or (ii) by reaction with a Grignard reagent R ⁴ -Mg-Hal (R ⁴ = CH ₂ - (CH ₂ ) _n -CR ¹ R ² Z ¹ , n is 2, 3, or 4 Z ¹ is as defined above and Hal is Cl or Br) in the presence of Li ₂ CuCl ₄ in a solvent (eg THF), and b) the compound from step (a) optionally (i) of diastereomers (eg (Ii) subjected to triplet-sensitized photoisomerization to the 5 (Z) isomer, (iii) desilylated (e.g. B with tetrabutylammonium fluoride), and (iv) otherwise removes protecting groups; where the order of these options is arbitrary. A process for the preparation of a compound of formula 1 according to claim 1, wherein: a) the side chain attached to C-20 in compound I from the 20 (S) and 20 (R) isomers of 1 (S), 3 (R ) -Bis (tert-butyldimethylsilyloxy) -20-formyl-9,10-secopregna-5 (E), 7 (E) 10 (19), 16-tetraene, either (i) by reaction with a reagent of the Wittig type (eg (EtO) ₂ P (O) -CH (Li) -CH = CH-COOCH ₃ ) and on final reaction of the resulting ester with an organometallic reagent (eg R ¹ Li) or (ii) by reaction with a Wittig type reagent

and subsequently reacting the resulting ketone with a reducing agent (eg NaBH ₄ ) in the presence of CeCl ₃ , and b) separating the compound from step (a) optionally (i) from diastereomers (eg by chromatography), (ii) a triplet subjecting sensitized photoisomerization to the 5 (Z) isomer, (iii) desilylating (eg with tetrabutylammonium fluoride), and (iv) otherwise removing protecting groups; where the order of these options is arbitrary. Intermediate for the synthesis of compounds of formula I and analogs thereof, namely: a) 1 (S), 3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (S) -hydroxy-9,10-secopregna-5 (E), 7 (E), 10 (19), 16-tetraene or the corresponding 20 (R) isomer, b) 1 (S), 3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (S) -p-toluenesulfonyloxymethyl 9,10-secopregna-5 (E), 7 (E), 10 (19), 16- tetraene or the corresponding 20 (R) isomer, c) 1 (S), 3 (E) -bis- (tert-butyldimethylsilyloxy) -20 (S) -formyl-9,10-secopregna-5 (E), 7 (E), 10 (19), 16-tetraene or the corresponding 20 (R) isomer. Pharmaceutical composition that is an effective Amount of one or more compounds of claims 1 to 3 together with pharmaceutically acceptable non-toxic carriers and / or aids. Pharmaceutical composition according to claim 7 in Form of a dosage unit containing 0.1 ppm by weight to 0.1% by weight of a Contains compound of formula I. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment or prophylaxis of hyperparathyroidism, especially associated with renal failure secondary Hyperparathyroidism, from diseases caused by an abnormal Cell differentiation and / or cell proliferation are characterized like cancer, leukemia, Myelofibrosis and psoriasis, from a number of disease states diabetes mellitus, hypertension, acne, alopecia, skin aging, AIDS, neurodegenerative diseases such as Alzheimer's disease, host-versus-graft reactions, Transplant rejection, inflammatory Diseases such as rheumatoid arthritis and asthma belong to prevention and / or treatment of steroid-induced skin atrophy and for promotion osteogenesis and for the treatment of osteoporosis.